Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.

Effects of Increased Central Cholinergic Activity on the Metabolic Challenge Induced by Submaximal Exercise in Rats: Adrenomedullary Secretion Influences.

AIM: The aim of this study was to assess the influence of adrenomedullary secretion on the plasma glucose, lactate, and free fatty acids (FFAs) during running exercise in rats submitted to intracerebroventricular (i.c.v.) injection of physostigmine (PHY). PHY i.c.v. was used to activate the central cholinergic system. METHODS: Wistar rats were divided into sham-saline (sham-SAL), sham-PHY, adrenal medullectomy-SAL, and ADM-PHY groups. The plasma concentrations of glucose, lactate, and FFAs were determined immediately before and after i.c.v. injection of 20 µL of SAL or PHY at rest and during running exercise on a treadmill. RESULTS: The i.c.v. injection of PHY at rest increased plasma glucose in the sham group, but not in the ADM group. An increase in plasma glucose, lactate, and FFAs mobilization from adipose tissue was observed during physical exercise in the sham-SAL group; however, the increase in plasma glucose was greater with i.c.v. PHY. Moreover, the hyperglycemia induced by exercise and PHY in the ADM group were blunted by ADM, whereas FFA mobilization was unaffected. CONCLUSION: These results indicate that there is a dual metabolic control by which activation of the central cholinergic pathway increases plasma glucose but not FFA during rest and exercise, and that this hyperglycemic response is dependent on adrenomedullary secretion.

Evolución de la cirugía bariátrica en Chile y el mundo / Bariatric Surgery's History in Chile and the World

Resumen La obesidad es reconocida como "la gran epidemia" del siglo XXI. Los primeros tratamientos fueron enfocados en el manejo médico, sin lograr los resultados esperados, por lo cual surge la cirugía bariátrica (CB) como la mejor alternativa. Inicialmente la obesidad se concibe como una figura de poder en el imperio egipcio, luego como enfermedad por Galeno e Hipócrates, reapareciendo más tarde como símbolo de fecundidad en Europa. Las primeras técnicas fueron el bypass yeyuno-colónico por Payne y De Wind modificado luego por Scopinaro, consolidándose más tarde como el bypass actual por Mason, Wittgrove e Higa. Por su parte, la gastrectomía en manga fue concebida por Gagner como puente de la derivación biliopancreática, pero dado sus excelentes resultados se consolida como técnica por sí sola. A su vez, la CB evidencia efectos metabólicos inesperados, posicionándose en la actualidad como el mejor tratamiento tanto para la obesidad como para el síndrome metabólico. En Chile la CB se inicia en 1986 con González del Hospital Van Buren con la experiencia en bypass yeyuno-ileal, continuando con Awad y Loehnert del Hospital San Juan de Dios. Luego se consolida con el desarrollo de la CB moderna tanto en la Universidad Católica como en la Universidad de Chile, llegando en la actualidad a ser un procedimiento ampliamente difundido en todo el país. El objetivo principal de la siguiente revisión es analizar el concepto de obesidad en la historia y la evolución de la CB en Chile y el mundo, rememorando sus inicios y destacando su constante desarrollo.

Obesity is recognized as "the great epidemic" of the 21st century. The first treatments were focused on medical management, failing to achieve the expected results, which is why bariatric surgery (BC) emerges as the best alternative. Obesity was initially conceived as a power figure in the Egyptian empire, later as a disease by Galen and Hippocrates, later reappearing as a symbol of fertility in Europe. The first techniques were the jejuno-colonic bypass by Payne and De Wind, later modified by Scopinaro, to finally consolidate as the current bypass by Mason, Wittgrove and Higa. For its part, sleeve gastrectomy was conceived by Gagner as a bridge for biliopancreatic diversion, but given its excellent results, it is consolidated as a technique by itself. In turn, BC shows unexpected metabolic effects, currently positioning itself as the best treatment for both obesity and metabolic syndrome. In Chile, BC started in 1986 with González at the Van Buren Hospital with his experience in jejuno-ileal bypass, continuing with Awad and Loehnert at the San Juan de Dios Hospital. Later, it was consolidated with the development of modern BC both at the Catholic University and at the University of Chile, currently becoming a widely disseminated procedure throughout the country. The main objective of the following review is to analyze the concept of obesity in history and the evolution of BC in Chile and the world, recalling its beginnings and highlighting its continuous development.

Experiencia en el uso de fibrina rica en plaquetas en pacientes con pie diabético / Experience in the use of platelet-rich fibrin in patients with diabetic foot

Resumen Objetivos: Describir las características clínicas y de laboratorio de los pacientes diabéticos tipo 2 (DM2) en tratamiento con fibrina rica en plaquetas (FRP) en el Hospital Clínico Herminda Martín entre los años 2014 y 2016. Materiales y Método: Se revisaron las fichas clínicas de todos los pacientes tratados con FRP en el policlínico de biomateriales en busca de los valores de HbA1c y glicemia, además de otras variables clínicas y de laboratorio que pudieren estar relacionadas con la evolución de las heridas de pie diabético. Se estableció tres grupos de comparación según el tiempo de cicatrización en cicatrización rápida (tiempo percentil 75). Resultados: De un universo de 147 pacientes con DM2 se reportan resultados de 85 (58%). El promedio de edad fue de 61 años, con una glicemia promedio de 243 g/dL y HbA1c de 9,4%. Presentaron un contaje plaquetario dentro de los parámetros normales (promedio 279 plaquetas/mm3). Se encontraron diferencias estadísticas en la escala de valoración de heridas, específicamente en la valoración del puntaje total, así como los parámetros como extensión, profundidad, y dolor entre los grupos de cicatrización rápida y lenta. No se evidenciaron diferencias en el nivel de HbA1c o glicemia en los grupos de cicatrización rápida o lenta, como tampoco en otras variables como edad, creatinina, recuento de plaquetas. Conclusión: No se encontró una asociación entre la velocidad de cicatrización y el nivel de HbA1c en individuos tratados con FRP.

Aims: To describe the clinical and laboratory characteristics of type 2 diabetic patients (DM2) treated with Platelet Rich Fibrin (FRP) at Hospital Clínico Herminda Martín between 2014 and 2016. Materials and Method: Analytical study that includes information from a secondary database. The clinical records of all patients treated with FRP at the Biomaterials Polyclinic were reviewed to search the HbA1c and glycemia values, as well as other clinical and laboratory variables that could be related to the evolution of diabetic foot wounds. Three comparison groups were established according to the healing time in rapid (time 75th percentile). Results: From a universe of 147 patients with DM2, results of 85 (58%) are reported. The average age in the included patients was 61 years. They had an average glycaemia of 243 g/dL, and HbA1c of 9.4%. They presented a platelet count within normal range (average 279 platelets/mm3). Statistical differences between the fast and slow healing groups were found in the wound assessment scale, specifically in the assessment of the total score, extension, depth, and pain. There were no differences in the HbA1c or glycemia level in the fast or slow healing groups, nor in other variables such as age, creatinine, and platelet count. Conclusion: No association was found between healing speed and HbA1c level in individuals treated with FRP.

Intracellular metabolic reprogramming mediated by micro-RNAs in differentiating and proliferating cells under non-diseased conditions.

Intracellular metabolic reprogramming is a critical process the cells carry out to increase biomass, energy fulfillment and genome replication. Cells reprogram their demands from internal catabolic or anabolic activities in coordination with multiple genes and microRNAs which further control the critical processes of differentiation and proliferation. The microRNAs reprogram the metabolism involving mitochondria, the nucleus and the biochemical processes utilizing glucose, amino acids, lipids, and nucleic acids resulting in ATP production. The processes of glycolysis, tricarboxylic acid cycle, or oxidative phosphorylation are also mediated by micro-RNAs maintaining cells and organs in a non-diseased state. Several reports have shown practical applications of metabolic reprogramming for clinical utility to assess various diseases, mostly studying cancer and immune-related disorders. Cells under diseased conditions utilize glycolysis for abnormal growth or proliferation, respectively, affecting mitochondrial paucity and biogenesis. Similar metabolic processes also affect gene expressions and transcriptional regulation for carrying out biochemical reactions. Metabolic reprogramming is equally vital for regulating cell environment to maintain organs and tissues in non-diseased states. This review offers in depth insights and analysis of how miRNAs regulate metabolic reprogramming in four major types of cells undergoing differentiation and proliferation, i.e., immune cells, neuronal cells, skeletal satellite cells, and cardiomyocytes under a non-diseased state. Further, the work systematically summarizes and elaborates regulation of genetic switches by microRNAs through predominantly through cellular reprogramming and metabolic processes for the first time. The observations will lead to a better understanding of disease initiation during the differentiation and proliferation stages of cells, as well as fresh approaches to studying clinical onset of linked metabolic diseases targeting metabolic processes.

Interleukin-26 Has Synergistic Catabolic Effects with Palmitate in Human Articular Chondrocytes via the TLR4-ERK1/2-c-Jun Signaling Pathway.

The inflammatory cytokine interleukin-26 (IL-26) is highly expressed in the serum and synovial fluid of patients with inflammatory arthritis. The effect of IL-26 on human articular chondrocytes (HACs) remains unclear. Obesity is associated with disability of patients with rheumatoid arthritis and disease activity in those with ankylosing spondylitis. The saturated free fatty acid palmitate with IL-1ß can synergistically induce catabolic effects in HACs. The aim of this study was to evaluate the effects of IL-26 and palmitate in HACs. In this study, palmitate markedly synergizes the IL-26-induced proinflammatory effects and matrix protease, including COX-2, IL-6, and MMP-1, in HACs via the toll-like receptor 4 (TLR4)-ERK1/2-c-Jun signal transduction pathway. The synergistic catabolic effects of palmitate and IL-26 were attenuated by inhibitors of TLR4 (TAK242), ERK1/2 (U0126), or c-Jun (SP600125) in HACs and cartilage matrix. In addition, metformin, a potential inhibitor of TLR4, also decreased expression of COX-2 and IL-6 induced by co-incubation with IL-26 and palmitate. IL-26 and palmitate synergistically induced expression of inflammatory and catabolic mediators, resulting in articular cartilage matrix breakdown. The present study also revealed a possible mechanism and therapeutic targets against articular cartilage degradation by increased saturated fatty acids in patients with inflammatory arthritis.

Associations between obesity, metabolic health, and the risk of breast cancer in East Asian women.

BACKGROUND: This study examined the associations between metabolic syndrome(MetS), obesity, their combination as a metabolic obesity phenotype, and the risk of breast cancer in East Asian postmenopausal women. METHODS: A total of 3,095,336 postmenopausal cancer-free women aged 40-79 years who underwent the National Health Insurance Service health examination between 2009 and 2010 were included. The incidence of invasive breast cancer was followed up until 2018. The presence of obesity (body mass index[BMI] ≥25 kg/m2), MetS, and each component of MetS was investigated. RESULTS: Obesity and MetS were associated with breast cancer risk, but when the effects of obesity and MetS were mutually adjusted, the associations were attenuated, especially for MetS. Only elevated fasting blood glucose levels and waist circumference increased the risk of breast cancer after adjusting for BMI. Compared to metabolically healthy normal-weight women, metabolically unhealthy normal-weight women, metabolically healthy obese, and metabolically unhealthy obese women had an increased risk of breast cancer. CONCLUSIONS: Obesity and MetS were independently associated with an increased risk of breast cancer in postmenopausal women, despite the relationship between MetS and breast cancer appearing to result from a partial association with BMI. Postmenopausal women should be encouraged to control their weight and metabolic health.

Scaling of joint mass and metabolism fluctuations in in silico cell-laden spheroids.

Variations and fluctuations are characteristic features of biological systems and are also manifested in cell cultures. Here, we describe a computational pipeline for identifying the range of three-dimensional (3D) cell-aggregate sizes in which nonisometric scaling emerges in the presence of joint mass and metabolic rate fluctuations. The 3D cell-laden spheroids with size and single-cell metabolic rates described by probability density functions were randomly generated in silico. The distributions of the resulting metabolic rates of the spheroids were computed by modeling oxygen diffusion and reaction. Then, a method for estimating scaling exponents of correlated variables through statistically significant data collapse of joint probability distributions was developed. The method was used to identify a physiologically relevant range of spheroid sizes, where both nonisometric scaling and a minimum oxygen concentration (0.04 mol⋅m-3) is maintained. The in silico pipeline described enables the prediction of the number of experiments needed for an acceptable collapse and, thus, a consistent estimate of scaling parameters. Using the pipeline, we also show that scaling exponents may be significantly different in the presence of joint mass and metabolic-rate variations typically found in cells. Our study highlights the importance of incorporating fluctuations and variability in size and metabolic rates when estimating scaling exponents. It also suggests the need for taking into account their covariations for better understanding and interpreting experimental observations both in vitro and in vivo and brings insights for the design of more predictive and physiologically relevant in vitro models.

More Metabolism!

To celebrate our Focus Issue, we asked a selection of researchers working on different aspects of metabolism what they are excited about and what is still to come. They discuss emerging concepts, unanswered questions, things to consider, and technologies that are enabling new discoveries, as well as developing and integrating approaches to drive the field forward.

Metabolic channeling: predictions, deductions, and evidence.

With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks operate with maximal catalytic efficiency and minimal interference? A logical answer was the postulate of metabolic channeling, which in its simplest embodiment assumes that the product generated by one enzyme passes directly to a second without diffusion into the surrounding medium. This tight coupling of activities might increase a pathway's metabolic flux and/or serve to sequester unstable/toxic/reactive intermediates as well as prevent their access to other networks. Here, we present evidence for this concept, commencing with enzymes that feature a physical molecular tunnel, to multi-enzyme complexes that retain pathway substrates through electrostatics or enclosures, and finally to metabolons that feature collections of enzymes assembled into clusters with variable stoichiometric composition. Lastly, we discuss the advantages of reversibly assembled metabolons in the context of the purinosome, the purine biosynthesis metabolon.

"Minimal metabolism": A key concept to investigate the origins and nature of biological systems.

The systems view on life and its emergence from complex chemistry has remarkably increased the scientific attention on metabolism in the last two decades. However, during this time there has not been much theoretical discussion on what constitutes a metabolism and what role it actually played in biogenesis. A critical and updated review on the topic is here offered, including some references to classical models from last century, but focusing more on current and future research. Metabolism is considered as intrinsically related to the living but not necessarily equivalent to it. More precisely, the idea of "minimal metabolism", in contrast to previous, top-down conceptions, is formulated as a heuristic construct, halfway between chemistry and biology. Thus, rather than providing a complete or final characterization of metabolism, our aim is to encourage further investigations on it, particularly in the context of life's origin, for which some concrete methodological suggestions are provided. Also see the video abstract here: https://youtu.be/DP7VMKk2qpA.

Protocol for setup and circadian analysis of inverted feeding in mice.

Inverted feeding is a paradigm to study synchronization of circadian clocks by feeding rhythm in tissues more directly. Here, we provide a protocol for performing inverted feeding in mice and analyzing circadian rhythmicity in mouse tissues. We describe setting up inverted feeding and performing tissue dissection, followed by RNA extraction and gene expression analysis, and lastly R software-based analysis of circadian rhythmicity. This protocol can be combined with the use of CircaMetDB database for mechanistic studies of inverted feeding. For complete details on the use and execution of this protocol, please refer to Xin et al. (2021).

Metabolipidomic profiling reveals an age-related deficiency of skeletal muscle pro-resolving mediators that contributes to maladaptive tissue remodeling.

Specialized pro-resolving mediators actively limit inflammation and support tissue regeneration, but their role in age-related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography-tandem mass spectrometry and tested whether treatment with the pro-resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro-resolving mediators 8-oxo-RvD1, resolvin E3, and maresin 1, as well as many anti-inflammatory cytochrome P450-derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro-inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E2 ) and 12-lipoxygenase (e.g., 12-hydroxy-eicosatetraenoic acid), but aged mice produced fewer markers of pro-resolving mediators including the lipoxins (15-hydroxy-eicosatetraenoic acid), D-resolvins/protectins (17-hydroxy-docosahexaenoic acid), E-resolvins (18-hydroxy-eicosapentaenoic acid), and maresins (14-hydroxy-docosahexaenoic acid). Similar absences of downstream pro-resolving mediators including lipoxin A4 , resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro-resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non-steroidal anti-inflammatory drugs.

Wild Bornean orangutans experience muscle catabolism during episodes of fruit scarcity.

Pronounced temporal and spatial variation in the availability of food resources can produce energetic deficits in organisms. Fruit-dependent Bornean orangutans face extreme variation in fruit availability and experience negative energy and protein balance during episodes of fruit scarcity. We evaluate the possibility that orangutans of different sexes and ages catabolize muscle tissue when the availability of fruit is low. We assess variation in muscle mass by examining the relationship between urinary creatinine and specific gravity and use the residuals as a non-invasive measure of estimated lean body mass (ELBM). Despite orangutans having a suite of adaptations to buffer them from fruit scarcity and associated caloric deficits, ELBM was lower during low fruit periods in all age-sex classes. As predicted, adult male orangutans had higher ELBM than adult females and immatures. Contrary to expectation, flanged and unflanged males did not differ significantly in ELBM. These findings highlight the precarity of orangutan health in the face of rapid environmental change and add to a growing body of evidence that orangutans are characterized by unique metabolic traits shaped by their unpredictable forest environment.

Association between cardiac high-energy phosphate metabolism and whole body metabolism in healthy female adults.

Decline in cardiac high-energy phosphate metabolism [phosphocreatine-to-ATP (PCr/ATP) ratio] and whole body metabolism increase the risk of heart failure and metabolic diseases. The aim of the present study was to assess the relationship between PCr/ATP ratio and measures of body metabolic function. A total of 35 healthy women (56+/-14.0 years of age) underwent cardiac 31P magnetic resonance spectroscopy to assess PCr/ATP ratio - an index of cardiac high-energy phosphate metabolism. Fasting and 2-hour glucose levels were assessed using oral glucose tolerance test. Indirect calorimetry was performed to determine oxygen consumption and resting metabolic rate. There were no significant relationships between PCr/ATP ratio and resting metabolic rate (r=-0.09, p=0.62), oxygen consumption (r=-0.11, p=0.54), fasting glucose levels (r=-0.31, p=0.07), and 2-hour plasma glucose (r=-0.10, p=0.58). Adjusted analysis for covariates including age, body mass index, fat mass, and physical activity, had no significant influence on the relationship between PCr/ATP ratio and body metabolism. In conclusion, the lack of relationship between cardiac PCr/ATP ratio, glucose control and metabolic rate may suggest that overall metabolic function does not influence cardiac high-energy phosphate metabolism.

Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence.

Host-derived fatty acids are an important carbon source for pathogenic mycobacteria during infection. How mycobacterial cells regulate the catabolism of fatty acids to serve the pathogenicity, however, remains unknown. Here, we identified a TetR-family transcriptional factor, FdmR, as the key regulator of fatty acid catabolism in the pathogen Mycobacterium marinum by combining use of transcriptomics, chromatin immunoprecipitation followed by sequencing, dynamic 13C-based flux analysis, metabolomics, and lipidomics. An M. marinum mutant deficient in FdmR was severely attenuated in zebrafish larvae and adult zebrafish. The mutant showed defective growth but high substrate consumption on fatty acids. FdmR was identified as a long-chain acyl-coenzyme A (acyl-CoA)-responsive repressor of genes involved in fatty acid degradation and modification. We demonstrated that FdmR functions as a valve to direct the flux of exogenously derived fatty acids away from ß-oxidation toward lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. Moreover, we found that FdmR suppresses degradation of long-chain acyl-CoAs endogenously synthesized through the type I fatty acid synthase. By modulating the supply of long-chain acyl-CoAs for lipogenesis, FdmR controls the abundance and chain length of virulence-associated lipids and mycolates and plays an important role in the impermeability of the cell envelope. These results reveal that despite the fact that host-derived fatty acids are used as an important carbon source, overactive catabolism of fatty acids is detrimental to mycobacterial cell growth and pathogenicity. This study thus presents FdmR as a potentially attractive target for chemotherapy.

Metabolic Shifts as the Hallmark of Most Common Diseases: The Quest for the Underlying Unity.

A hyper-specialization characterizes modern medicine with the consequence of classifying the various diseases of the body into unrelated categories. Such a broad diversification of medicine goes in the opposite direction of physics, which eagerly looks for unification. We argue that unification should also apply to medicine. In accordance with the second principle of thermodynamics, the cell must release its entropy either in the form of heat (catabolism) or biomass (anabolism). There is a decreased flow of entropy outside the body due to an age-related reduction in mitochondrial entropy yield resulting in increased release of entropy in the form of biomass. This shift toward anabolism has been known in oncology as Warburg-effect. The shift toward anabolism has been reported in most diseases. This quest for a single framework is reinforced by the fact that inflammation (also called the immune response) is involved in nearly every disease. This strongly suggests that despite their apparent disparity, there is an underlying unity in the diseases. This also offers guidelines for the repurposing of old drugs.

Reciprocal regulation of cellular mechanics and metabolism.

Metabolism and mechanics are intrinsically intertwined. External forces, sensed through the cytoskeleton or distortion of the cell and organelles, induce metabolic changes in the cell. The resulting changes in metabolism, in turn, feed back to regulate every level of cell biology, including the mechanical properties of cells and tissues. Here we examine the links between metabolism and mechanics, highlighting signalling pathways involved in the regulation and response to cellular mechanosensing. We consider how forces and metabolism regulate one another through nanoscale molecular sensors, micrometre-scale cytoskeletal networks, organelles and dynamic biomolecular condensates. Understanding this cross-talk will create diagnostic and therapeutic opportunities for metabolic disorders such as cancer, cardiovascular pathologies and obesity.